HSC Derived MDSC for the Prevention of GHVD Without Suppressing GvL

描述（由申请方提供）：移植物抗宿主病（GVHD）是异基因造血干细胞（HSC）移植后发病率和死亡率的主要原因，HSC移植是恶性血液病患者的既定治疗方法。目前减少GVHD的策略包括T细胞耗竭和免疫抑制药物，这与肿瘤复发、机会性感染和/或毒性的风险增加有关。显然需要内在地作用于免疫系统的新方法。在这方面，天然存在的免疫抑制细胞，骨髓源性抑制细胞（MDSC），最近获得了相当大的关注。MDSC通过多种机制抑制T细胞应答，例如iNOS、过氧化物酶和活性氧。我们证明了MDSC在体内诱导肿瘤抗原特异性T调节细胞和T细胞无能。我们的初步结果表明，MDSC具有几个有吸引力的属性作为辅助细胞，以抑制GVHD，而不显着损害移植物抗白血病/淋巴瘤（GVL）的小鼠模型，在嵌合体和长期生存的结果建立。初步研究表明，大量的MDSC可以在外周动员和扩增。该提议的目的是一种优化的方案，通过该方案可以动员和扩增MDSC，并测试动员的MDSC在抑制同种免疫应答而不显著抑制期望的GVL活性方面的适用性。根据我们初步研究的结果，我们假设：（i）可以从骨髓动员大量MDSC，表现出与肿瘤宿主衍生的对应物相当的抑制功能;（ii）GA可以调节MDSC的分化和抑制功能，从而增强MDSC治疗预防GVHD的功效;（iii）来源于动员方案的MDSC可以强烈抑制由CD4 T细胞介导的同种异体应答并诱导Treg扩增，但对CD8 T细胞表现出较小的抑制作用;（iv）MDSC治疗优先消除主要活化的T细胞并偏向于CD44 + CD62L-记忆性CD8和CD4 T细胞的选择性扩增，从而预防GVHD而不显著损害GVL活性;（V）肿瘤细胞的RAE-1（NKG2D配体）表达在照射后增强，这导致对NKG2D + CD8 T细胞和/或NK细胞杀伤的敏感性增加。本研究的目的有三：1）动员并扩增骨髓来源的抑制性细胞，并评价动员的MDSC联合GA治疗对GVHD的预防作用; 2）研究动员的MDSC抑制GVHD的机制; 3）研究支持MDSC优先抑制GVHD而不显著损害GVL活性的机制。现有的肿瘤模型。这些信息将为MDSC在人体中的动员和扩展提供基础和科学原则，可用于临床环境中进行未来的临床试验。

DESCRIPTION (provided by applicant): Graft versus host disease (GVHD) is the leading cause of morbidity and mortality following allogeneic hematopoietic stem cell (HSC) transplantation, an established therapy for patients with hematological malignancies. Current strategies to diminish GVHD include T cell depletion and immunosuppressive drugs, which are associated with an increased risk of tumor relapse, opportunistic infection, and/or toxicity. Novel approaches acting intrinsically on the immune system are clearly needed. In this regard, naturally occurring immunosuppressive cells, myeloid-derived suppressor cells (MDSCs), have recently gained considerable attention. MDSCs suppress T-cell responses through multiple mechanisms, e.g. iNOS, arginase, and reactive oxygen species. We demonstrated that MDSC induced tumor antigen specific T regulatory cells and T-cell anergy in vivo. Our preliminary results indicate that MDSCs have several attractive attributes as helper cells to inhibit GVHD without significantly compromising graft-versus-leukemia/lymphoma (GVL) in a murine model that results in the establishment of chimerism and long-term survival. The preliminary study showed that a significant number of MDSCs could be mobilized and expanded in the periphery. The objective of this proposal is to an optimized protocol by which MDSCs can be mobilized and expanded and to test the applicability of mobilized MDSCs in suppressing the allo-immune response without significantly suppressing the desirable GVL activity. Based on the results of our preliminary studies, we hypothesize that: (i) A significant amount of MDSC, exhibiting comparable suppressive functions as the tumor-host-derived counterpart, can be mobilized from bone marrow; (ii) GA can modulate differentiation and suppressive function of MDSC, thereby enhancing the efficacy of MDSC treatment in preventing GVHD; (iii) MDSCs derived from mobilization protocols can strongly suppress allo-responses mediated by CD4 T cells and induce Treg expansion, but exhibit less suppressive effect on CD8 T cells; (iv) MDSC treatment preferentially eliminates primarily activated T cells and skews toward the selective expansion of CD44+CD62L- memory CD8 and CD4 T cells, thereby preventing GVHD without significantly compromising the GVL activity; (v) RAE-1 (NKG2D ligand) expression by tumor cell is enhanced upon irradiation, which leads to increased susceptibility to killing by NKG2D+ CD8 T cells and/or NK cells. Three specific aims will be pursued: 1) Mobilize and expand myeloid-derived suppressor cells from bone marrow into the periphery and assess the prevention of GVHD by mobilized MDSCs in combination with GA treatment; 2) Study the mechanisms underlying the inhibition of GVHD mediated by mobilized MDSC; 3) Study the mechanisms underpinning the preferential suppression of GVHD by MDSC without significantly compromising GVL activity in pre-existing tumor models. The information will provide the basis and scientific principles for the mobilization and expansion of MDSC in human that can be used in clinical settings for future clinical trials.